Population Pharmacokinetic-pharmacodynamic (PK-PD) Study of 9 Broad-Spectrum Anti-infective Agents in the Cerebro Spinal Fluid (CSF) of Brain Injured Patients With an External Ventricular Drainage (EVD).

Nosocomial Central Nervous System infections are difficult to treat and an early appropriate therapy can improve prognosis. The two main reasons for treatments failure are the difficulty to reach high concentrations of antibiotics (ATB) in CNS because of brain barriers (BB), and the emergence of Multi-Drug-Resistant (MDR) pathogens that require high ATB concentrations for being killed. Therefore a better knowledge of ATB CNS distribution and PK-PD characteristics is essential for efficiency of treatments and to avoid resistance progression. Because of BB and cerebrospinal fluid (CSF) turnover, unbound (active) concentrations of ATB in CSF are frequently much lower than corresponding plasma concentrations, which therefore may not be used to predict efficacy. However except for patients with EVD, CSF access is difficult. Overall the litterature about ATB distribution within CSF exist but PK-PD publications are rarer. Especially for Broad Spectrum ATB which are recommended in case of invasive infection in ICU patients due to MDR pathogens such as Acinetobacter baumanii, extended spectrum ß-Lactamase producing (ESBL) pathogens or Multiresistant Staphylococcus aureus.

Furthermore, measuring ATB concentrations within the CSF at certain time-points is necessary but not sufficient to predict antimicrobial efficacy. First PK modelling is required to describe the full CSF concentrations versus time profiles. Then targets must be obtained from literature or determined for the relevant PD index, which may be, depending of the antibiotic, Time over Minimal Inhibitrice Concentration (T>MIC), Area Under the Curve over MIC (AUC/MIC) or peak concentration over MIC (Cmax/MIC). Eventually Monte-Carlo simulations can be conducted to predict the probability of target attainment according to various dosing regimens to find the optimal one.

The goal of this multicenter population PK-PD study is to characterize CSF distribution and challenge recommended dosing regimens of 8 ATB indicated in CNS infections (vancomycin, daptomycin, ceftazidime, meropenem, colistin, linezolid, piperacillin-tazobactam and ceftaroline) and to study the Cefepime diffusion in the CSF, known to be highly neurotoxic.